The disfiguring, dysfunctional hypertrophic scar (HS) in the highly strained tissue of a badly burned patient leaves an indelible impression. It is not well understood how high tissue-tension promotes HS, but it is clear that environmental strain regulates fibroblast gene expression, fibroblast alignment and extracellular matrix (ECM) morphology through integrin linked cell-cell and cell ECM interactions. Conformational changes in integrins mediate focal adhesion kinase (FAK) activation and subsequent phosphorylation of tyrosine residues. Therefore, FAK and associated proteins likely play a pivotal role in HS formation. The broad long-term objective of the project is to unravel the signaling pathways underlying strain induced HS growth. The hypothesis to be tested is mechanical strain promotion of HS formation in healed wounds. A novel in vitro mechanical strain device and tight-skin mouse wound-healing model will be used to investigate three aims: (1) Compare temporal phosphorylation patterning of beta1 integrin, FAK, and talin and myosin light chain kinase activation in mechanically strained HS, normal human scar and normal human dermal fibroblasts (NHDF). (2) Describe how tyrosine kinase inhibition affects phosphorylation of beta1, integrin, FAK, and talin tyrosine phosphorylation and MLCK activity in physically strained HS, normal human scar and NHDF. (3) Document how systemic administration of the tyrosine phosphatase inhibitor, orthovanadate, affects HS-like nodule myofibroblast formation and wound contraction in tight-skin mouse wounds and compare to matched normal mouse wounds.